X-129567266-C-T

Variant names:

• chrX-129567266-C-T
• rs137853839
• NM_000276.4:c.1369C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000276.4(OCRL):​c.1369C>T​(p.Arg457Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000185 in 1,082,057 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R457G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

Genes affected

OCRL (HGNC:8108): (OCRL inositol polyphosphate-5-phosphatase) This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OCRL Gene-Disease associations (from GenCC):

• Dent disease type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4	c.1369C>T	p.Arg457Cys	missense_variant	Exon 14 of 24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.1372C>T	p.Arg458Cys	missense_variant	Exon 14 of 24		NP_001305713.1
OCRL	NM_001587.4	c.1369C>T	p.Arg457Cys	missense_variant	Exon 14 of 23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.1369C>T	p.Arg457Cys	missense_variant	Exon 14 of 24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.1369C>T	p.Arg457Cys	missense_variant	Exon 14 of 23	1		ENSP00000349635.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1082057 Hom.: 0 Cov.: 27 AF XY: 0.00000286 AC XY: 1 AN XY: 349667

African (AFR) AF: 0.00 AC: 0 AN: 26076

American (AMR) AF: 0.00 AC: 0 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19262

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.00 AC: 0 AN: 53748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00000242 AC: 2 AN: 827484

Other (OTH) AF: 0.00 AC: 0 AN: 45559

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lowe syndrome Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg457 amino acid residue in OCRL. Other variant(s) that disrupt this residue have been observed in individuals with OCRL-related conditions (PMID: 21031565; Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt OCRL protein function. This variant has not been reported in the literature in individuals affected with OCRL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 457 of the OCRL protein (p.Arg457Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.71		Loss of MoRF binding (P = 0.0253);Loss of MoRF binding (P = 0.0253);
MVP		0.97
MPC		2.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.94
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853839; hg19: chrX-128701243; COSMIC: COSV63979992;